Introduction
Cardiac disease has historically been considered uncommon in rabbits, with only occasional case reports and anecdotal documentation in the literature.1 Others, however, have described it as a common condition,2–4 leading to confusion as to the prevalence of cardiac disease in companion rabbits. Rabbits have been used as models for atherosclerosis, endocarditis, and drug-induced cardiomyopathies in other species.5–7 However, there appear to be few published reports of cardiac disease in companion rabbits, and the reports that have been published have generally been limited to case reports.8–16 Two case series4,17 describing cardiac disease in rabbits are available, but the total number of rabbits examined are not described, making it impossible to determine the prevalence of cardiac disease. Cardiac and cardiovascular disease are broadly discussed in general review articles3,18,19 and textbooks,1,20–22 but much of the information presented is extrapolated from small animal medicine.
Many published reports23–28 regarding cardiovascular disease in rabbits focus on diagnostic tests, including radiography, echocardiography, and ECG, and techniques for measuring blood pressure, and there is a paucity of information regarding the treatment and prognosis of rabbits with cardiovascular disease.29,30 Therefore, the objectives of the study reported here were to determine the epidemiological features of cardiovascular disease in rabbits examined at a veterinary teaching hospital and characterize clinical diagnostic findings, treatments, necropsy findings, and survival time.
Materials and Methods
Case selection
An electronic search of the medical records of the William R. Pritchard Veterinary Medical Teaching Hospital was performed to identify rabbits examined between January 1, 2001, and December 31, 2018, in which a cardiac disorder was diagnosed. The following keywords were used: murmur, echo, echocardiogram, ECG, cardiomyopathy, endocarditis, cardiomegaly, myocardial, arrhythmia, myocarditis, pericardial, arteriosclerosis, atherosclerosis, stenosis, valvular, mitral, tricuspid, aortic, pleural effusion, edema, ascites, congestive, and heart failure. Rabbits were included in the study if a cardiac disease or disorder had been diagnosed on the basis of echocardiographic, ECG, or necropsy findings. Patients with murmurs due to other conditions and patients without any echocardiographic abnormalities were excluded. Rabbits in which cardiovascular disease was suspected on the basis of radiographic findings but not confirmed by means of echocardiography, ECG, or necropsy were also excluded. The prevalence of cardiovascular disease in rabbits was calculated by dividing the number of rabbits with cardiac disease by the total number of rabbits examined during the study period. The date of first visit was used for analyses; if the date of first visit was prior to 2001, the date of first visit was classified in the 2001 to 2010 category.
Medical records review
Information extracted from the medical records of rabbits included in the study consisted of, when available, signalment, age, weight, body condition score (scored on a scale from 1 [severely emaciated] to 9 [severely overweight]), sex, neuter status, and breed. Records were reviewed to identify cardiac diagnosis, presenting complaint, physical examination findings, diet, radiographic findings, results of other imaging modalities (ie, CT and ultrasonography), blood pressure measurement, whether CHF was present (characterized by pulmonary edema, pleural effusion, ascites, or pericardial effusion), medications (those for the treatment of cardiac disease and others), response to treatment, other treatment methods (ie, thoracocentesis, radiation therapy, and integrative medicine), adverse treatment effects, hematologic and serum biochemical abnormalities, results of other diagnostic testing, follow-up time, survival time, and cause of death. If owners provided a range of drug dosages, the mean dosage was calculated and used in analyses. If multiple dosage changes were made for a single drug, the highest or lowest change from the initial dosage was evaluated. Response to treatment was categorized as no change, improvement, or progression (0 to 1 week, 2 weeks, 1 month, or > 1 month). Dates of recheck examinations were rounded to the closest time interval (0 to 1 week, 2 weeks, 1 month, or > 1 month).
Echocardiography and ECG
All initial echocardiographic and ECG examinations were performed by a board-certified veterinary cardiologist or a veterinary cardiology resident under the supervision of a board-certified veterinary cardiologist. Echocardiography was performed with a 12- to 4-mHz, sector-array transducera; standard 2-D, M-mode, color Doppler, and spectral Doppler echocardiographic images were obtained. Measurements were performed as previously described.23 All available studies were reviewed by one of the authors (CG-H) using an offline workstationb and published body weight–appropriate reference values for echocardiographic variables in rabbits, when available.23,24,28 Objective and subjective findings were assessed together to assign a diagnosis considered to most likely be responsible for observed cardiac changes. For example, if both systolic dysfunction and valvular insufficiency were present, chamber dilation (left ventricle or left atrium), severity of dysfunction, and valve appearance were taken into account to render a single, final diagnosis of either degenerative mitral valve disease or dilated cardiomyopathy. If ≥ 1 echocardiographic examination was available, the diagnosis was made on the basis of the overall course of the disease and the most severe changes noted. Left-sided and right-sided cardiac enlargement were graded as absent, mild, moderate, or severe. Mitral, tricuspid, and aortic insufficiency were graded as absent, trivial, mild, moderate, or severe. Systolic dysfunction was noted if present; relative systolic dysfunction was defined as normal to low systolic function (ie, fractional shortening) in the face of ventricular dilatation. The presence and characteristics of arrhythmias and relative heart rates were described. Additionally, the presence of ascites, pleural effusion, and pericardial effusion identified during echocardiography were described. A diagnosis of CHF was made on the basis of echocardiographic cardiac chamber enlargement and relevant concurrent fluid accumulation (edema or effusion). If echocardiographic images were not available for rereview, only the final diagnoses and presence or absence of findings were evaluated.
Necropsy
Necropsy reports, including gross and histologic diagnoses, were evaluated when available. All necropsies were performed by a board-certified veterinary pathologist or a veterinary pathology resident under direct supervision of a board-certified veterinary pathologist. If available, tissues relating to the cardiovascular system and final cardiac diagnosis were reevaluated by one of the authors (KK) to verify original diagnoses. Cardiovascular diagnoses were then classified as cardiomyopathy, myocarditis, arteriosclerosis (including atherosclerosis), valvular disease, or congenital disease. If > 1 category of cardiovascular disease was present, the predominant or clinically most important was chosen.
Survival time
Survival time was calculated from the time of clinical diagnosis of cardiac disease or, for rabbits in which cardiac disease was diagnosed postmortem, the time when clinical signs consistent with heart disease (eg, murmur, arrhythmia, ascites, or effusion) were first observed. If no clinical signs consistent with cardiac disease were reported, survival time was not evaluated.
Statistical analysis
The Shapiro-Wilk test was used to assess whether continuous data were normally distributed. Mean and SD were reported for normally distributed data, and median and range were reported for data that were not normally distributed. Descriptive statistics were calculated for signalment, clinical signs, clinical findings, concurrent diseases, treatment, diagnostic test results, and postmortem findings. Ninety-five percent CIs were calculated with Clopper-Pearson binomial proportions when > 1 rabbit was affected. A χ2 test was used to compare prevalence of cardiac disease between male and female rabbits. The Kaplan-Meier product-limit method was used to estimate cardiac disease–specific survival time, defined as time in days from cardiac disease diagnosis until death or euthanasia attributable to cardiac disease. Animals that were still alive, had been lost to follow-up, or had died or been euthanatized because of noncardiac causes were censored on the last date they were known to be alive. Commercial software was used for all statistical analyses.c–f Values of P ≤ 0.05 were considered significant.
Results
Patient population
Fifty-nine rabbits with cardiac disease met the criteria for inclusion in the study. In total, 2,249 rabbits were examined at the William R. Pritchard Veterinary Medical Teaching Hospital during the study period; therefore, overall prevalence of cardiac disease in rabbits was 2.6%. Seventeen rabbits examined between 2001 and 2010 and 42 rabbits examined between 2011 and 2018 were included. The prevalence of cardiac disease in rabbits was 1.6% (17/1,053; 95% CI, 0.94% to 2.6%) from 2001 to 2010 and 3.5% (42/1,196; 95% CI, 2.5% to 4.7%) from 2011 to 2018.
An age was listed for 54 of the 59 rabbits included in the study, with the remaining 5 rabbits identified only as adult. Mean ± SD age was 6.8 ± 3.1 years. More males (38/59 [64.4%; 95% CI, 50.9% to 76.5%]) than females (21/59 [35.6%; 95% CI, 23.6% to 49.1%]) were included. Twenty-two of the 38 males (57.9%; 95% CI, 40.8% to 73.7%) and 18 of the 21 females (85.7%; 95% CI, 63.7% to 97%) were neutered. More male than female rabbits were examined during the study years, and although the prevalence of cardiac disease among male rabbits (3.5%; 95% CI, 2.5% to 4.8%) was higher than the prevalence among female rabbits (2.4%; 95% CI, 1.5% to 3.7%), these values were not significantly (P = 0.17) different.
Breed information was available for 43 rabbits. Lop-eared rabbits (n = 13 [30.2%; 95% CI, 17.2% to 46.1%]) were most common and included undescribed lop-eared rabbits (8), French Lops (1), Holland Lops (2), and Mini Lops (2). Dwarf rabbits were next most common (n = 10 [23.3%; 95% CI, 11.8% to 38.6%]), including undescribed dwarf rabbits (6) and Netherland Dwarfs (4), followed by New Zealand Whites (7 [16.3%; 95% CI, 6.8% to 30.7%]). The remaining breeds that were represented consisted of Lionhead (3 [7%]), Angora (2 [5%]), Flemish Giant (2 [5%]), Rex (2 [5%]), Dutch (1 [2.3%]), Polish (1 [2.3%]), Californian (1 [2.3%]), and Himalayan (1 [2.3%]).
Body weight was provided for 58 of the rabbits; for these rabbits, mean ± SD body weight was 2.5 ± 1.14 kg. Body condition score was available for 51 rabbits; median body condition score was 4 (range, 1 to 7). Diet information was available for 41 rabbits. Most animals ate grass hay (n = 26 [63%]) and pellets (40 [98%]). Other items in the diets included leafy green vegetables (n = 26 [63.4%]), fruit (11 [26.8%]), assorted treats (7 [17.1%]), carrots (4 [9.8%]), critical care formulas (3 [7.3%]), and alfalfa hay (2 [4.9%]).
History and physical examination findings
Information on presenting complaints and physical examination findings was available for 54 rabbits. The remaining 5 animals died shortly after arriving at the hospital or at home prior to presentation. The most common physical examination findings included a heart murmur (n = 25 [46.3%; 95% CI, 32.6% to 60.4%]) or an arrhythmia (22 [40.7%; 95% CI, 27.6% to 55%]). Murmurs were graded on a scale from 1 to 6, with a median score of 3 (range, 1 to 4).
Common physical examination findings potentially related to cardiac or cardiovascular disease included tachypnea or dyspnea (n = 13 [24.1%; 95% CI, 13.5% to 37.6%]), hyporexia or anorexia (13 [24.1%; 95% CI, 13.5% to 37.6%]), lethargy (10 [18.5%; 95% CI, 9.3% to 31.4%]), diarrhea or a change in feces (10 [18.5%; 95% CI, 9.3% to 31.4%]), muscle wasting (9 [16.7%; 95% CI, 7.9% to 29.3%]), ambulatory deficits or lameness (6 [11.1%; 95% CI, 4.2% to 22.6%]), dehydration (5 [9.3%]), altered mentation (5 [9.3%]), harsh lung sounds (5 [9.3%]), cyanosis or muddy mucous membranes (2 [3.7%]), muffled heart sounds (2 [3.7%]), and subcutaneous edema (2 [3.7%]).
Common physical examination findings unrelated to cardiac or cardiovascular disease included dental disease (n = 20 [37%]), pododermatitis (12 [22.2%]), otitis (6 [11.1%; 95% CI, 4.2% to 22.6%]), cataracts (5 [9.3%]), ocular discharge (5 [9.3%]), decreased thoracic compliance (4 [7.4%]), pale mucous membranes (4 [7.4%]), hypothermia (3 [5.6%]), and vestibular signs (3 [5.6%]).
Hematologic and plasma biochemical findings
A CBC was performed in 29 animals. Leukocytosis (definedg as a WBC count > 10,030 WBCs/µL) was present in 4 (13.8%; 95% CI, 3.9% to 31.2%) animals (WBC count range, 10,140 to 24,330 WBCs/µL). Polycythemia was present in 1 animal, which had a PCV of 63%. Anemia (definedg as a PCV < 30%) was present in 10 (34.5%; 95% CI, 17.9% to 54.3%) animals (PCV range, 16% to 29%). Other abnormalitiesg included heterophilia (> 4,400 heterophils/µL; n = 5 [17.2%]), hyperfibrinogenemia (> 300 mg/dL; 4 [13.8%]), leukopenia (< 900 WBCs/µL; 3 [10.3%]), monocytosis (> 800 monocytes/µL; 3 [10.3%]), and toxic neutrophils (1 [3%]).
A plasma biochemistry panel was performed in 33 animals. Abnormalitiesg included high creatine kinase activity (> 950 U/L; n = 10 [30.3%; 95% CI, 15.6% to 48.7%]), azotemia (BUN > 30 mg/dL or creatinine > 1.5 mg/dL; 9 [27.3%; 95% CI, 13.3% to 45.5%]), high alanine aminotransferase activity (> 127 U/L; 7 [21.2%; 95% CI, 9% to 38.9%]), high aspartate aminotransferase activity (> 52 U/L; 6 [18.2%; 95% CI, 7% to 35.5%]), hypoproteinemia (< 5.9 g/dL; 6 [18.2%; 95% CI, 7% to 35.5%]), hyperglycemia (> 197 mg/dL; 5 [15.2%]), hyperphosphatemia (> 5.0 mmol/L; 4 [12.1%]), high γ-glutamyltransferase activity (> 18 U/L; 3 [9.1%]), hypoglycemia (< 109 mg/dL; 3 [9.1%]), high alkaline phosphatase activity (> 126 U/L; 3 [9.1%]), hyperkalemia (> 5.7 mmol/L; 3 [9.1%]), and hypokalemia (< 3.5 mmol/L; 2 [6.1%]). One animal had hypernatremiag (> 148 mmol/L) and another had hyperchloremiag (> 109 mmol/L). Of the 6 animals with hypoproteinemia, 5 had effusion and CHF. Of the 7 animals with a high alanine aminotransferase activity, 5 had CHF and 2 had hepatitis or hepatopathy at necropsy.
Radiographic, abdominal ultrasonographic, and CT findings
Diagnostic imaging other than echocardiography was performed in 44 animals, including radiography (n = 39, including 4 animals in which radiography was performed by the referring veterinarian and images were sent for review), abdominal ultrasonography (15), and CT (7). The most common imaging findings related to the cardiovascular system were subjective cardiomegaly (n = 19 [43.2%; 95% CI, 38.4% to 59%]), peritoneal effusion (12 [27.3%; 95% CI, 15% to 42.8%]), pleural effusion (11 [25.0%; 95% CI, 13.2% to 40.3%]), bronchointerstitial lung pattern (8 [18.2%; 95% CI, 8.2% to 32.7%]), distended vena cava or hepatic veins (6 [13.6%; 95% CI, 5.2% to 27.4%]), and an interstitial or alveolar lung pattern (5 [11.4%; 95% CI, 3.8% to 24.6%]). Noncardiovascular findings included osteoarthritis and intervertebral disk disease (n = 15 [34.1%]), otitis (8 [18.2%]), dental disease (8 [18.2%]), mediastinal mass effect (6 [13.6%]), and other mass or nodule (5 [11.4%]). Less common findings included lymphadenopathy (n = 4 [9.1%]), gastric or intestinal dilation (4 [9.1%]), renal changes (2 [4.5%]), and lens luxation, urolithiasis, vessel mineralization, uterine abnormality, atelectasis, or fracture (1 [2.3%] each).
ECG findings
Electrocardiography was performed in 19 of the 22 animals that had arrythmias. Both supraventricular arrhythmias (n = 15 [78.9%; 95% CI, 54.4% to 93.9%]) and ventricular arrhythmias (12 [63.2%; 95% CI, 38.4% to 83.7%]) were present. Eight (42.1%; 95% CI, 20.2% to 66.5%) animals had both supraventricular and ventricular arrhythmias. Supraventricular arrhythmias consisted of atrial premature complexes (n = 8 [42.1%; 95% CI, 20.2% to 66.5%]), atrial fibrillation (5 [26.3%; 95% CI, 9.2% to 51.2%]), and supraventricular tachycardia (3 [15.8%; 95% CI, 3.4% to 39.6%]). Ventricular arrhythmias consisted of ventricular premature complexes (n = 9 [47.4%; 95% CI, 24.5% to 71.1%]), ventricular tachycardia (2 [10.5%; 95% CI, 1.2% to 33.1%]), and ventricular bigeminy (1 [5.3%; 95% CI, 0.1% to 26%]). Four (21.1%; 95% CI, 6.1% to 45.6%) rabbits had atrioventricular block.
Echocardiographic findings
Echocardiography was performed in 37 of the 59 rabbits, and for 30 of the 37, echocardiographic studies were available for retrospective review. Right-sided cardiac enlargement (n = 19 [51.4%; 95% CI, 34.4% to 68.1%]) and left-sided cardiac enlargement (20 [54.1%; 95% CI, 36.9% to 70.5%]) were both present. Ten (27.0%; 95% CI, 12.8% to 44.1%) animals had both right-sided and left-sided cardiac enlargement. Right-sided cardiac enlargement was classified as mild (n = 4), moderate (6), or severe (6); severity was not classified in the remaining 3 animals because echocardiographic studies were not available for review. Left-sided cardiac enlargement was classified as mild (n = 1), moderate (5), or severe (7) but could not be classified in the remaining 7 animals because echocardiographic studies were not available for review.
More than trivial mitral valve regurgitation was present in 18 (60.0%; 95% CI, 40.6% to 77.3%) of the 30 animals for which echocardiographic studies were available for review (mild, n = 10; moderate, 4; and severe, 6), more than trivial tricuspid valve regurgitation was present in 16 (53.3%; 95% CI, 34.3% to 71.7%) animals (mild, 9; moderate, 5; and severe, 2), and more than trivial aortic valve insufficiency was present in 8 (26.7%; 95% CI, 12.3% to 45.9%) animals (mild, 6; and moderate, 2). Systolic dysfunction was present in 11 (36.7%; 95% CI, 19.9% to 56.1%) of the 30 animals, including 4 that had relative systolic dysfunction. Aortic dilation was noted in 3 (10.0%; 95% CI, 2.1% to 26.5%) animals.
Overall, the most common diagnosis for the 37 rabbits that underwent echocardiography was degenerative valve disease (n = 15 [40.5%; 95% CI, 24.8% to 57.9%]), followed by dilated cardiomyopathy (7 [18.9%; 95% CI, 8% to 35.2%]) and unclassified cardiomyopathy (4 [10.8%; 95% CI, 3% to 25.4%]). Of the 15 rabbits with degenerative valve disease, 5 had systolic dysfunction. Other diagnoses included restrictive cardiomyopathy (n = 3 [8.1%]) and hypertrophic cardiomyopathy (2 [5.4%]). One rabbit had a ventricular septal defect, and another had a double-chambered right ventricle. Two rabbits had an undetermined cardiomyopathy. Two other rabbits had normal echocardiographic findings but abnormal postmortem findings; one had endocarditis and pulmonary hypertension, and the other had an intra-atrial thrombus.
Twenty-four (64.9%) of the 37 animals that underwent echocardiography were sedated. Sixteen (66.7%) were sedated with a combination of midazolam and butorphanol (n = 10), hydromorphone (2), or oxymorphone (4), and 8 (33.3%) were sedated with midazolam alone.
Other diagnostic test results
Other diagnostic tests that were performed included bubble contrast echocardiography (n = 1), measurement of serum taurine (1) or digoxin (1) concentration, and Holter monitoring (1). Serum cardiac troponin I concentration was measured in 3 rabbits, and concentrations were 0.02, 0.13, and 0.16 ng/mL. Fluid analysis was performed on free abdominal or pleural fluid from 7 rabbits; 6 had transudates and 1 had a chylous effusion.
Necropsy
Necropsy reports for 35 rabbits were available for review. The most common primary cardiac diagnosis was cardiomyopathy (n = 14 [40.0%; 95% CI, 23.9% to 57.9%]), followed by myocarditis (10 [28.6%; 95% CI, 14.6% to 46.3%]) and arteriosclerosis (9 [25.7%; 95% CI, 12.5% to 43.3%]). Primary valvular disease was uncommon (n = 1 [2.9%]). There were no congenital defects found at necropsy. One rabbit was found not to have any cardiac abnormalities on necropsy, although the right side of the heart was dilated secondary to a thymoma.
Fibrosis (n = 12), cardiac hypertrophy (4) or dilation (3), and necrosis (5) were the most common findings in the 14 rabbits with primary cardiomyopathy. Cardiomyopathy was classified as mild (n = 2), moderate (5), or severe (5) but was not classified in the remaining 2 rabbits. Secondary diagnoses in rabbits with primary cardiomyopathy included myocarditis (n = 4) and valvular disease (1). One animal with primary cardiomyopathy had smooth-muscle hypertrophy of the coronary vessels suggestive of hypertension; however, blood pressure was not measured prior to death in this rabbit.
The type of inflammation in the 10 rabbits with myocarditis was classified as lymphocytic (n = 7), heterophilic (4), histiocytic (3), or eosinophilic and granulomatous (1); 5 rabbits had ≥ 1 type of inflammation. Severity of myocarditis was described in 8 rabbits as mild (n = 7) or severe (1). The 1 animal with eosinophilic myocarditis had intralesional ascarids within the myocardium and concurrent Baylisascaris infestation of the brain and spinal cord. Myocardial necrosis or mineralization was present in 2 rabbits with myocarditis. Secondary cardiovascular diagnoses in rabbits with myocarditis included degenerative valvular disease (n = 2), arteriosclerosis (1), and cardiomyopathy (1).
Lesions in the 9 rabbits with arteriosclerosis involved the aorta (n = 4), other arteries and arterioles (5), and cardiac valves (1). Other vessels affected by arteriosclerosis included the intrarenal and pulmonary arteries. In all but 1 rabbit, arteriosclerosis was evident as mineralization with minimal detectable lipid. The remaining rabbit had severe, generalized atherosclerosis with foamy macrophages and acicular clefts indicative of cholesterol deposition in arteries throughout the body, including the coronary arteries. Secondary diagnoses in the rabbits with arteriosclerosis included cardiomyopathy (n = 4) and myocarditis (3).
Of the 13 rabbits that underwent both echocardiography and necropsy, 7 had similar echocardiographic and necropsy diagnoses and 6 had diagnoses that differed. For the 6 rabbits that had diagnoses that differed, 2 had normal echocardiographic findings but severe aortic arteriosclerosis with myocarditis or cardiomyopathy on necropsy. Two rabbits had echocardiographic diagnoses of degenerative valve disease, but one had cardiomyopathy with arteriosclerosis (Figures 1 and 2) and the other had cardiac dilation secondary to a thymoma on postmortem examination. One rabbit had dilated cardiomyopathy diagnosed on echocardiographic examination but had myocarditis diagnosed on necropsy. Finally, 1 rabbit did not have evidence of cardiac disease on echocardiographic examination but had cardiomyopathy on necropsy. The mean time between echocardiography and necropsy for these 6 rabbits was 37 days (range, 2 to 163 days).
Right lateral (A) and ventrodorsal (B) radiographic images of a 9-year-old spayed female rabbit. On the lateral image, there is severe cardiomegaly with dorsal deviation of the trachea and a diffuse bronchointerstitial lung pattern. On the ventrodorsal image, there is cardiomegaly and a diffuse bronchointerstitial lung pattern.
Citation: Journal of the American Veterinary Medical Association 259, 7; 10.2460/javma.259.7.764
Right lateral (A) and ventrodorsal (B) radiographic images of a 9-year-old spayed female rabbit. On the lateral image, there is severe cardiomegaly with dorsal deviation of the trachea and a diffuse bronchointerstitial lung pattern. On the ventrodorsal image, there is cardiomegaly and a diffuse bronchointerstitial lung pattern.
Citation: Journal of the American Veterinary Medical Association 259, 7; 10.2460/javma.259.7.764
Right lateral (A) and ventrodorsal (B) radiographic images of a 9-year-old spayed female rabbit. On the lateral image, there is severe cardiomegaly with dorsal deviation of the trachea and a diffuse bronchointerstitial lung pattern. On the ventrodorsal image, there is cardiomegaly and a diffuse bronchointerstitial lung pattern.
Citation: Journal of the American Veterinary Medical Association 259, 7; 10.2460/javma.259.7.764
Standard 2-D echocardiographic image (A) and a photograph of the heart obtained at necropsy (B) from the rabbit in Figure 1. Severe left ventricular (LV), left atrial (LA), and right atrial (RA) enlargement along with severe mitral valve (MV) regurgitation and aortic insufficiency are seen on the echocardiographic image. Findings were considered consistent with advanced, degenerative, mitral valve disease. At necropsy, severe, generalized cardiomegaly was seen, and histologic examination of cardiac tissues revealed severe chronic fibrosis and severe mineralization of the aorta and aortic valve.
Citation: Journal of the American Veterinary Medical Association 259, 7; 10.2460/javma.259.7.764
Standard 2-D echocardiographic image (A) and a photograph of the heart obtained at necropsy (B) from the rabbit in Figure 1. Severe left ventricular (LV), left atrial (LA), and right atrial (RA) enlargement along with severe mitral valve (MV) regurgitation and aortic insufficiency are seen on the echocardiographic image. Findings were considered consistent with advanced, degenerative, mitral valve disease. At necropsy, severe, generalized cardiomegaly was seen, and histologic examination of cardiac tissues revealed severe chronic fibrosis and severe mineralization of the aorta and aortic valve.
Citation: Journal of the American Veterinary Medical Association 259, 7; 10.2460/javma.259.7.764
Standard 2-D echocardiographic image (A) and a photograph of the heart obtained at necropsy (B) from the rabbit in Figure 1. Severe left ventricular (LV), left atrial (LA), and right atrial (RA) enlargement along with severe mitral valve (MV) regurgitation and aortic insufficiency are seen on the echocardiographic image. Findings were considered consistent with advanced, degenerative, mitral valve disease. At necropsy, severe, generalized cardiomegaly was seen, and histologic examination of cardiac tissues revealed severe chronic fibrosis and severe mineralization of the aorta and aortic valve.
Citation: Journal of the American Veterinary Medical Association 259, 7; 10.2460/javma.259.7.764
CHF
Twenty of the 59 (33.9%; 95% CI, 22.1% to 47.4%) rabbits had CHF diagnosed antemortem by means of radiography (n = 6) or echocardiography (10) or at necropsy (4). In these animals, right-sided or left-sided CHF was diagnosed on the basis of the location of fluid accumulation and the most clinically important atrial enlargement. Six (30%; 95% CI, 11.9% to 55.3%) animals had right-sided CHF, 5 (25%; 95% CI, 8.7% to 49.1%) had left-sided CHF, and 7 (35%; 95% CI, 15.4% to 59.2%) had biventricular CHF. In the remaining 2 (10%; 95% CI, 1.2% to 31.7%) animals, the type of heart failure was undetermined, but 1 of these 2 animals was suspected to have arrhythmogenic CHF. Nine (45%; 95% CI, 23.1% to 68.5%) of the 20 rabbits with CHF had arrhythmias.
Effusion was a common finding in rabbits with CHF, with pleural effusion (n = 14 [70%; 95% CI, 45.7% to 88.1%]) being the most common, followed by pericardial effusion (12 [60%; 95% CI, 36.1% to 80.8%]) and peritoneal effusion (10 [50%; 95% CI, 27.2% to 72.8%]). Fourteen (70%; 95% CI, 45.7% to 88.1%) rabbits had effusion involving > 1 cavity, including 4 rabbits with tricavitary effusion, 4 with pleural and pericardial effusion, 2 with pleural and peritoneal effusion, and 4 with pericardial and peritoneal effusion. Of the 6 rabbits with right-sided CHF, 5 had pleural effusion, 3 had pericardial effusion, and 3 had peritoneal effusion; 2 had an alveolar or interstitial lung pattern. Of the 5 rabbits with left-sided CHF, 4 had pleural effusion, 3 had pericardial effusion, and 2 had peritoneal effusion; 2 had an alveolar or interstitial lung pattern. Of the 7 rabbits with biventricular CHF, 4 had pleural effusion, 6 had pericardial effusion, and 4 had peritoneal effusion; 3 had a bronchointerstitial lung pattern. One rabbit with undetermined CHF had pleural effusion, and the other had peritoneal effusion.
Information on time from diagnosis of CHF to death was available for 13 rabbits. For these rabbits, median time from diagnosis of CHF to death was 68 days (95% CI, 4 to 411 days; Figure 3).
Kaplan-Meier graph of time from diagnosis of CHF to death for 13 rabbits. Median time from diagnosis of CHF to death was 68 days (95% CI, 4 to 411 days).
Citation: Journal of the American Veterinary Medical Association 259, 7; 10.2460/javma.259.7.764
Kaplan-Meier graph of time from diagnosis of CHF to death for 13 rabbits. Median time from diagnosis of CHF to death was 68 days (95% CI, 4 to 411 days).
Citation: Journal of the American Veterinary Medical Association 259, 7; 10.2460/javma.259.7.764
Kaplan-Meier graph of time from diagnosis of CHF to death for 13 rabbits. Median time from diagnosis of CHF to death was 68 days (95% CI, 4 to 411 days).
Citation: Journal of the American Veterinary Medical Association 259, 7; 10.2460/javma.259.7.764
Concurrent diseases
The most common concurrent diseases identified antemortem or at necropsy were dental disease (n = 22 [37.3%]); renal disease (15 [25.4%]); liver disease, including hepatitis, necrosis, and liver-lobe torsion (14 [23.7%]); lower airway disease (14 [23.7%]); neoplasia (13 [22%]); osteoarthritis (12 [20.3%]); pododermatitis (12 [20.3%]); and otitis (10 [17%]). Eight of the 13 animals with neoplasia had thymic tumors. In 14 of the 15 rabbits with renal disease, the diagnosis was made or confirmed at necropsy. One remaining animal had severe azotemia (BUN, > 180 mg/dL; creatinine, 6.7 mg/dL) prior to death, and a necropsy was not performed. Histopathologic diagnoses in the 14 rabbits with renal disease that underwent necropsy consisted of interstitial nephritis (n = 8), pyelitis or pyelonephritis (3), glomerular sclerosis (3), fibrosis (2), tubular mineralization (2), renal infarcts (2), tubular necrosis (2), and hydronephrosis (2), with 6 animals having > 1 diagnosis.
For 13 of the 14 rabbits with lower airway disease, the diagnosis was made at necropsy. In the remaining rabbit, the diagnosis was made on the basis of radiographic findings and clinical signs. Only 2 of the 13 rabbits in which the diagnosis was made at necropsy had histopathologic evidence of bacteria. The remaining had a variety of inflammatory lesions characterized as eosinophilic (n = 1), histiocytic (6), lymphocytic (1), suppurative-heterophilic (7), emphysematous (1), or necrotizing (2). Three animals had aspiration pneumonia with intralesional foreign material.
Treatment
In total, 20 (33.9%; 95% CI, 22.1% to 47.4%) of the 59 animals received cardiac medications. The most common drug used was furosemide (n = 15; dosage range, 1 to 4 mg/kg, PO or SC, q 8, 12, or 24 h), followed by enalapril (14; dosage range, 0.18 to 0.5 mg/kg, PO, q 12 or 24 h) and pimobendan (12; dosage range, 0.2 to 1 mg/kg, PO, q 8, 12, or 24 h). Other drugs used consisted of diltiazem (n = 2; 24 mg/kg, PO, q 12 h and 4 mg/kg, PO, q 8 h), spironolactone (2; 2 mg/kg, PO, q 12 h and 1 mg/kg, PO, q 24 h), atenolol (2; 1.5 mg/kg, PO, q 12 h and 0.3 mg/kg, PO, q 24 h), sotalol (1; 1.7 mg/kg, PO, q 12 h), digoxin (1; 0.03 mg/kg, PO, q 12 h), and hydrochlorathiazide (1; 1 mg/kg, PO, q 12). During the course of treatment, the dose or frequency of administration was increased in 7 animals treated with furosemide, 5 animals treated with pimobendan, and 1 animal treated with atenolol. Other treatments provided included thoracocentesis (n = 6) and oxygen therapy (2). One animal underwent biweekly thoracocentesis for a total of 6 treatments.
Adverse treatment effects were reported in 4 animals and included hypokalemia (n = 2), soft feces (1), azotemia (1), and leukopenia (1). The animal that developed soft feces received furosemide, enalapril, and pimobendan in addition to sucralfate, calcium gluconate, and fluids administered SC. The animal that developed azotemia was receiving furosemide, enalapril, pimobendan, and meloxicam. The azotemia resolved after meloxicam and enalapril administration was discontinued, and the furosemide dosage was decreased from 2 mg/kg every 8 hours to 1 mg/kg every 12 hours. Both animals that developed hypokalemia were receiving enalapril and furosemide. The animal that developed leukopenia was receiving pimobendan, furosemide, spironolactone, and meloxicam. Spironolactone was discontinued, but a follow-up CBC was not performed.
Seven animals received fluids SC; 4 of these animals had or developed CHF. Two of the rabbits that received fluids SC had CHF and were given fluids for concurrent diseases (gastrointestinal stasis and renal disease). The other 2 rabbits were given fluids SC, and CHF was diagnosed 1 to 4 days later.
The most common concurrent medications unrelated to cardiovascular disease were antimicrobials (n = 15) and analgesics (20). Analgesics included meloxicam (n = 19), tramadol (7), gabapentin (2), and an opioid (1). Chemotherapy (doxorubicin, lomustine, l-asparaginase, vinblastine, and cyclophosphamide) was administered to 1 animal; this patient had cardiomyopathy with fibrosis on necropsy. In total, 5 animals received radiation therapy for thymomas. Two of these animals had cardiomyopathy on necropsy, 3 had degenerative mitral valve disease on echocardiography, and 2 had arrhythmias (1 with ventricular premature contractions and 1 with atrial premature contractions).
Survival analysis
Overall, 26 animals died, 21 were euthanatized, and 6 were alive at the time of final follow-up. The remaining 6 rabbits were lost to follow-up. Cause of death or euthanasia was determined for 47 rabbits, with cardiovascular disease being the most common cause (n = 23), followed by pneumonia (8) and neoplasia (7). Four of the 7 rabbits with neoplasia had thymomas, 2 had lymphoma, and 1 had peritoneal carcinomatosis.
Fourteen (23.7%) of the 59 rabbits died or were euthanatized at the time of cardiac disease diagnosis for reasons unrelated to cardiac disease, 4 (6.8%) died or were euthanatized at the time of cardiac disease diagnosis for reasons attributed to cardiac disease, and 5 (8.5%) were lost to follow-up immediately following cardiac disease diagnosis.
Follow-up of ≥ 1 day was available for the remaining 36 (61.0%) animals. Of these, 7 (11.9%) were alive or lost to follow-up a median of 182 days (range, 10 to 757 days) after cardiac disease was diagnosed. Nineteen (32.2%) rabbits died or were euthanatized during the follow-up period because of cardiac disease, and 10 (16.9%) rabbits died or were euthanatized because of noncardiac conditions. Survival times ranged from 1 to 2,353 days after cardiac disease was diagnosed. Median cardiac disease–specific survival time for the 36 rabbits for which follow-up information was available was 306 days (95% CI, 68 to 466 days; Figure 4). Median survival time for all 59 rabbits was 160 days (95% CI, 43 to 411 days).
Kaplan-Meier graph of cardiac disease–specific survival time for 36 rabbits with cardiac disease. One rabbit survived for 2,353 days, but the graph is truncated at 800 days because of the instability of estimates based on a single animal. Median cardiac disease–specific survival time for the 36 rabbits was 306 days (95% CI, 68 to 466 days).
Citation: Journal of the American Veterinary Medical Association 259, 7; 10.2460/javma.259.7.764
Kaplan-Meier graph of cardiac disease–specific survival time for 36 rabbits with cardiac disease. One rabbit survived for 2,353 days, but the graph is truncated at 800 days because of the instability of estimates based on a single animal. Median cardiac disease–specific survival time for the 36 rabbits was 306 days (95% CI, 68 to 466 days).
Citation: Journal of the American Veterinary Medical Association 259, 7; 10.2460/javma.259.7.764
Kaplan-Meier graph of cardiac disease–specific survival time for 36 rabbits with cardiac disease. One rabbit survived for 2,353 days, but the graph is truncated at 800 days because of the instability of estimates based on a single animal. Median cardiac disease–specific survival time for the 36 rabbits was 306 days (95% CI, 68 to 466 days).
Citation: Journal of the American Veterinary Medical Association 259, 7; 10.2460/javma.259.7.764
For 30 rabbits, follow-up information was available for ≥ 7 days after cardiac disease was diagnosed. Of those 30 rabbits, 12 had progression of cardiac disease, 8 had no change in their cardiac disease, and 2 had an improvement in their cardiac disease. Disease progression could not be determined for the remaining 8 animals. One animal treated for suspected endocarditis had normal echocardiographic findings 334 days later.
Discussion
In the present study, we found that the prevalence of cardiovascular disease in rabbits examined at a veterinary teaching hospital between 2001 and 2018 was 2.6% (59/2,249). Previous literature1–3,19 has stated that cardiovascular disease is either common or uncommon in rabbits; however, to our knowledge, no previous research discusses the prevalence of the condition, resulting in generalized statements that may be misleading. Approximately 10% of dogs and cats have cardiovascular disease,31,32 which is higher than the prevalence found in the present study. Also, in the present study, the prevalence of cardiovascular disease was higher among rabbits examined between 2011 and 2018 than among rabbits examined between 2001 and 2010. It is likely that this higher prevalence was due to an increased recognition of clinical signs and expansion of diagnostic capabilities. Additionally, with the advancement of treatments available for rabbits with other conditions, their lifespan may be prolonged.
Although the prevalence of cardiovascular disease did not differ significantly between sexes, we found that cardiovascular disease was diagnosed in more male than female rabbits in the present study. The lack of significance may have been due to the relatively low number of rabbits with cardiovascular disease, compared with the total number of rabbits seen during the study period. In humans, certain cardiovascular diseases, such as heart failure, cardiomyopathy, and coronary artery disease, are more common in males than females, and age-related differences also occur.33 In rats, mice, macaques, and dogs, females appear to have a reduced risk or lower incidence of cardiovascular disease as well.34,35 Sex differences have also been described in experimental studies of atherosclerosis. Depending on the method to induce the lesion, strain of rabbit, and duration of the study, lesions have been reported to be more common in males36 or females37 or to not differ in prevalence between sexes.38 Both age and sex likely play a role in the development of cardiovascular disease in companion, primarily neutered, rabbits.39
Most of the rabbits with cardiovascular disease in the present study were lop-eared rabbits, dwarf rabbits, and New Zealand White rabbits. Textbooks have suggested that larger-breed rabbits such as New Zealand White rabbits and French Lops may be more predisposed to developing cardiovascular disease,20 and certain breeds, including New Zealand White rabbits, may also have a higher incidence of atherosclerosis.40,41 Because of the format of our medical record system, total numbers of each of these breeds examined during the study years could not be accurately determined. Subjectively, however, these rabbit breeds are commonly seen in practice, and the higher number of rabbits of these breeds with cardiovascular disease may reflect their commonness rather than represent a true increased incidence in these breeds.
Most of the clinical signs related to cardiovascular disease seen in this study, such as tachypnea or dyspnea, hyporexia or anorexia, lethargy, diarrhea or a change in feces, and muscle wasting, were likely secondary to effusion or edema and decreased cardiac output; most of these clinical signs have previously been described in other animals with cardiovascular disease. However, ambulatory deficits were an unexpected finding. It is possible that, for rabbits in the present study, hind limb weakness was a manifestation of generalized weakness or a result of peripheral neuropathy or poor oxygenation, or it may not have been related to cardiac disease at all. Many of the rabbits with cardiovascular disease in the present study had a low body condition (median score, 4/9). In dogs, weight loss or cardiac cachexia is common with CHF and may affect survival rate.42 Nutritional support in rabbits with cardiovascular disease and CHF should be considered as part of the management and treatment plan. A heart murmur (25/54) and arrhythmia (22/54) were also common signs in the present study. In other species, a murmur, especially of higher grade, is often associated with echocardiographic abnormalities or structural disease.43,44 Although we did not compare patients with and without a murmur, echocardiography would seem to be recommended in all rabbits with a heart murmur.
Common hematologic and plasma biochemical findings in the present study were anemia, hypoproteinemia, high creatine kinase activity, azotemia, and high alanine aminotransferase activity. Possible causes for the anemia included chronic inflammatory disease and renal insufficiency.45 The animals in the present study had a relatively high prevalence of renal disease as well as inflammatory conditions such as pneumonia. Similarly, both anemia and azotemia are common in dogs with valvular disease.46 Creatine kinase is an enzyme found in the heart as well as other muscles, and plasma activities may increase with cardiac disease. However, it is an insensitive marker, and plasma activities may increase as a result of a wide variety of muscular injuries and other diseases.47 Most of the rabbits with hypoproteinemia in the present study had evidence of effusion or CHF. Thus, the hypoproteinemia was likely due to effusion or hemodilution, but enteral or renal loss was also possible.48–50 Additionally, rabbits with a high alanine aminotransferase activity commonly had right-sided or biventricular CHF, which can be associated with passive congestion of the liver and hepatocellular insult. One rabbit had evidence of hypercholesterolemia on necropsy with lipid deposits in multiple tissue, but an antemortem chemistry panel was not performed. On necropsy, this rabbit had arteriosclerosis. It is important to note that plasma concentrations of triglycerides and specific lipoproteins were not measured in the rabbits in the present study, but such measurements may be considered in future cases.
Cardiomegaly was a common radiographic finding and was seen in 19 (49%) of 39 rabbits in the present study. In all instances, the diagnosis was made by a board-certified veterinary radiologist or veterinary radiology resident on the basis of subjective interpretation. References for normal radiographic cardiovascular size in rabbits are available, with vertebral heart score reportedly ranging from 7.1 to 8.5,27,51 but determining the vertebral heart score in rabbits can be challenging because the cranial margin of the heart may be partially obscured by the thymus.23 Additionally, although cardiomegaly was identified in some rabbits, specific chamber enlargement was not identified during examination of radiographic images. In cats, radiography is an insensitive tool to diagnose specific chamber enlargement as well, and cardiomegaly alone is commonly seen.52
In addition to the classic interstitial or alveolar lung pattern seen with CHF, a bronchointerstitial lung pattern was a common pulmonary radiographic finding in the present study. Of the 20 animals with CHF, 4 had an alveolar or interstitial lung pattern and 3 had a bronchointerstitial lung pattern. However, an alveolar or bronchointerstitial lung pattern can be seen with other lower airway diseases, such as pneumonia. In dogs, the classic presentation of pulmonary edema is an alveolar or unstructured interstitial pattern,53 but in cats, cardiogenic pulmonary edema varies in radiographic appearance and may be patchy and perihilar, rather than diffuse interstitial.52 One animal with a bronchointerstitial lung pattern on radiographs was confirmed to have biventricular CHF and pulmonary edema on necropsy. Given our findings, an alveolar or bronchointerstitial lung pattern in a rabbit with other signs or indications of cardiovascular decompensation should raise concerns for pulmonary edema. An unexpected finding was the presence of an alveolar pattern in rabbits with CHF. Some of these rabbits had evidence of pneumonia on physical examination or necropsy, which would be a more likely explanation for this radiographic change.
Both supraventricular and ventricular arrhythmias were common in the present study. Additionally, several animals had > 1 type of arrhythmia. Arrhythmias in rabbits have been uncommonly documented in the literature and have mainly been discussed in relation to CHF.1,9,20,54 Arrhythmias can have primary cardiovascular and noncardiovascular etiologies. Nine (41%) of the 22 rabbits in the present study with arrhythmias developed or had CHF but determining the cause of arrhythmias not associated with cardiovascular disease was beyond the scope of this study. Nevertheless, our findings suggested that rabbits may be an arrhythmogenic species and that arrhythmias may be a common sequela of cardiovascular disease in rabbits.
The most common echocardiographic diagnosis in our study was degenerative valve disease, and valve diseases, including degenerative and infectious valve disease, have been previously described in rabbits.12,14,55 Degenerative valve disease was also the most common antemortem diagnosis in a previous case series4 of 13 rabbits with cardiac disease, but postmortem examinations were not available. Although degenerative valve disease was a common antemortem diagnosis in our study, it was an uncommon primary necropsy diagnosis. Dilated cardiomyopathy was the second most common echocardiographic diagnosis and the most common necropsy finding. One possible cause of this discrepancy was the varying times between antemortem diagnosis and death, and there may have been progression of cardiovascular disease during this period. In addition, necropsy does not take into account the physiologic activity of the heart or the interplay between function and anatomic structure. Valve disease and valvular regurgitation can occur concurrently with cardiomyopathy.56 Additionally, some of the rabbits with echocardiographic evidence of degenerative valve disease also had evidence of systolic dysfunction. Volume overload secondary to degenerative valve disease could progress to dilated cardiomyopathy. Conversely, dilated cardiomyopathy and other cardiomyopathies can lead to valvular regurgitation. Importantly, distinguishing between degenerative valve disease and cardiomyopathy antemortem may not alter treatment recommendations, as both conditions benefit from administration of inotropic drugs early in the disease process.57–59
Other diagnostic tests were uncommonly performed in rabbits included in the present study. A transudate was the most common type of effusion found, and all rabbits with transudates had CHF, which fits with the major type of effusion found in other species.60 Diagnostic tests such as Holter monitoring for cardiac arrhythmias and bubble contrast echocardiography for diagnosis of cardiac shunting have not previously been reported in rabbits. Serum cardiac troponin I concentration was measured in 3 rabbits, and although commercial assays for cardiac troponin I concentration have not been validated for rabbits, they have been shown to be highly sensitive and specific for myocardial injury in other species. Overall, cardiac troponin I concentration tends to be well conserved across species, and values < 0.1 ng/mL (dogs, horses, and birds) to < 0.16 ng/mL (cats) are generally considered normal.61–63 Validation studies are required before clinical recommendations can be made on interpreting cardiac troponin I concentrations in rabbits.
Cardiomyopathy was the most common necropsy finding in the present study. Cardiomyopathy may be primary or develop secondary to drugs, toxins, inflammatory conditions, infectious diseases, metabolic causes, stress, inherited diseases, endocrine diseases, and nutritional deficiencies.44,64–66 Hypertrophic, restrictive, and dilated cardiomyopathy have all been reported anecdotally in rabbits,20 and in a previous case series4 of 17 companion rabbits, dilated cardiomyopathy was the most common cardiac disease diagnosed antemortem. Cardiomyopathy and myocardial lesions have been experimentally induced in rabbits by feeding a vitamin E–deficient diet67 and by administering ketamine and xylazine.68 One animal in the present study received doxorubicin. This animal had normal echocardiographic findings prior to initiation of chemotherapy but left anterior fascicular block suggestive of myocardial fibrosis was present on ECG following administration of 3 doses of doxorubicin, and myocardial fibrosis was confirmed at necropsy. The lesions in this animal were not reflective of the dilated cardiomyopathy typically seen with doxorubicin toxicosis but may have represented early lesions. Rabbits have limited collateral coronary circulation and are therefore predisposed to ischemia secondary to coronary vasoconstriction.69 In fact, norepinephrine and catecholamines can cause extensive myocardial injury in rabbits.70,71
Arteriosclerosis was an unexpected finding in the present study. Arteriosclerosis is a broad term that includes atherosclerosis and arteriosclerosis.72 Rabbits are used as an animal experimental model of dietary-induced atherosclerosis because they quickly develop hypercholesterolemia when fed a high-cholesterol diet and certain laboratory rabbit strains also have heritable hypercholesterolemia.5,73 However, previous reports of this condition in companion rabbits are rare.11 In our study, arteriosclerosis was more commonly diagnosed than atherosclerosis. The pathogenesis and etiology of arteriosclerosis in companion rabbits is unknown. Possible etiologies may be systemic hypertension, the unique calcium metabolism of rabbits, or a dietary factor.74–76 Arteriosclerosis can lead to pressure overload and poor perfusion, which could result in the clinical appearance of primary cardiomyopathy antemortem.77 Only 1 animal in our study had antemortem evidence of mineralization of the aorta. Thus, radiographs can be considered for antemortem monitoring for atherosclerosis but may be an insensitive diagnostic tool.
Our findings suggested that right-sided, left-sided, and biventricular CHF occur with similar frequencies in rabbits. Pleural effusion was a common finding and was documented in 14 of the 20 rabbits with CHF. This was similar to the case in cats, which can develop pleural effusion with left-sided CHF.53 It is presumed that pleural effusion in cats is due to elevated left atrial pressures, and left atrial dysfunction has been found to be a contributing factor in the development of pleural effusion in cats.78 It is possible that a similar mechanism exists in rabbits.
Concurrent diseases were frequent in the present study. Renal disease was present in 15 (25.4%) of the 59 rabbits, which was a higher percentage than percentages of rabbits with urinary tract disease (10%) and renal insufficiency (3%) reported previously.79 In other species, concurrent cardiac and renal disease has been termed cardiorenal syndrome,80 defined as a condition in which failure of one organ (ie, heart or kidney) leads to dysfunction of the other. Kidney injury can occur because of reduced renal perfusion resulting from decreased cardiac output, renal congestion, and activation of the renal-angiotensin-aldosterone and sympathetic systems. Kidney dysfunction can lead to fluid overload, electrolyte changes, decreased systolic function, and neurohormonal stimulation that can in turn affect cardiac function.80,81 Although cardiorenal syndrome has not yet been described in rabbits, our findings suggested that it may occur. Lower airway disease (ie, pneumonia) was also a common (14/59 [23.7%]) concurrent disease in the rabbits of the present study. Although pneumonia has been previously reported in rabbits, it tends to be less common than upper respiratory tract infections.82 To our knowledge, there are no reports of an association between pneumonia and cardiovascular disease in veterinary species. In humans, cardiac complications can occur following community-acquired pneumonia, including CHF, arrhythmias, and myocardial infarcts.83 Five of the rabbits with pneumonia in our study also had myocarditis. Additionally, in humans there is an increased risk of cardiovascular disease for up to 5 years following hospitalization for sepsis or pneumonia.84 Whether this risk occurs in rabbits is unknown. Pneumonia seen in our study may have been unrelated to cardiovascular disease and may simply have represented the expected prevalence of pneumonia in this population.
Treatment for cardiovascular disease and CHF in the rabbits included in the present report was extrapolated from treatments reported for other species because dosages have not been established for many cardiovascular drugs used in rabbits, pharmacokinetic and pharmacodynamic data for rabbits are lacking, and the few studies29,30 involving rabbits used as experimental models for human patients offer little clinical practicality. Owing to the variety of dosages, number of changes in dosages, and small number of rabbits, the effect of any particular drug on prognosis could not be determined. However, 12 of 30 rabbits in which disease progression could be assessed had progression of cardiovascular disease despite treatment. This may have been due to the progressive nature of cardiovascular disease and the lack of research on therapeutic dosages for cardiovascular drugs in rabbits. Adverse effects associated with treatment were uncommon in the present study, and the adverse effects that were reported, including hypokalemia and azotemia, were similar to the adverse effects reported for dogs and cats treated with diuretics.31 The single rabbit with leukopenia was not reevaluated after administration of spironolactone was discontinued, but this drug has been associated with leukopenia in humans.85
Five animals in the present study received radiation therapy for thymic neoplasia. Four of these animals underwent echocardiography, and 2 underwent necropsy. Both animals that underwent necropsy had primary cardiomyopathy, which was also diagnosed echocardiographically in 1 animal. One was described as having fibrosing cardiomyopathy with secondary myocarditis, and the other had degenerative cardiomyopathy with myocarditis. An additional 2 rabbits that received radiation therapy had arrhythmias. Adverse radiation effects in humans include pericardial injury, conduction abnormalities, ischemic heart disease, myocarditis, atherosclerosis, and cardiomyopathy.86 In human patients undergoing radiation therapy, reevaluation of the radiation plan to account for tumor shrinkage and cranial shift of the heart is recommended to minimize the risk of adverse effects.87 Owing to the close proximity of the thymus to the heart and the relatively small thoracic cavity of rabbits, cardiac injury secondary to radiation therapy should be considered a possibility. However, no direct association between radiation therapy and development of cardiomyopathy could be identified in the rabbits in our study. Additionally, these rabbits underwent multiple anesthetic and sedative episodes, which may have contributed to the development or occurrence of cardiac disease.
Overall, the median survival time for rabbits in the present study was lower than that reported for other species.59,88 In cats with CHF secondary to hypertrophic cardiomyopathy, the median survival time is 103 days without and 626 days with pimobendan treatment.88 In dogs with degenerative valve disease, the median survival time is 902 days from the time of diagnosis and 345 days once CHF develops.59,89 The low survival time in our study may have been due to the lack of follow-up in some patients, the lack of pharmacokinetic and pharmacodynamic data to guide drug treatment of cardiac disease, challenges medicating rabbits, insufficient data in the medical records, or concurrent diseases. Because rabbits are prey animals, subclinical disease or a lack of clinical signs until severe disease is present can be expected. Establishing a diagnosis earlier in disease processes may prolong survival times in rabbits.
The present study provided what was, to our knowledge, the first report of the prevalence of cardiovascular disease in domestic rabbits examined at a veterinary teaching hospital. In our study, 2.6% of animals examined between 2001 and 2018 had cardiovascular disease, indicating that it is a condition that is not uncommonly encountered. The presence of a heart murmur, arrhythmia, or cardiomegaly should be considered as an indication for echocardiography, ECG, or both. The presence of a bronchointerstitial, interstitial, or alveolar lung pattern on radiographs may be suggestive of pulmonary edema related to cardiac disease or CHF in rabbits. Rabbits appear to develop both right- and left-sided CHF, and pleural effusion was the most common finding in these cases. Our results provided evidence of the need for additional studies regarding the diagnosis and treatment of cardiovascular disease in rabbits.
Acknowledgments
No third-party funding or support was received in connection with this study or the writing or publication of the manuscript. The authors declare that there were no conflicts of interest.
The authors thank Michelle Giuffrida, VMD, MS, for assistance with statistical calculations.
Footnotes
Philips iE33 Ultrasound, Philips Healthcare, Andover, Mass.
Syngo Dynamics, Siemens Medical Solutions, Malvern, Pa.
EpiTools software, AusVet, Bruce, ACT, Australia.
JASP, version 0.9, JASP, Amsterdam, Netherlands.
Stata, release 14, StataCorp, College Station, Tex.
Excel, Microsoft Corp, Richmond, Wash.
University of California-Davis Veterinary Medical Teaching Hospital clinical chemistry and hematology reference intervals. May 21, 2016.
Abbreviations
| CHF | Congestive heart failure |
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